Cephalosporins

ABSTRACT

WHEREIN R1 is an acyl group, R2 and R3 represent hydrogen, a lower alkyl group, carboxylic group, amino group, dimethylamino group or hydroxymethyl group, respectively, or R2 and R3 may be bonded to form -NH-CH N- group. These cephalosporins have a broad antimicrobial spectrum. They are, in particular, effective against colitis germs (Escherichia coli) at a lower concentration. Example thereof include 7-(2-thienylacetamido)-3(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4 -carboxylic acid, 7(phenyl-acetamido)- 3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em4-carboxylic acid, 7-(phenoxyacetamido)3-(2-oxopyrimidin-4ylthio)-methylceph-3-em-4-carboxylic acid and 7-(2-thienylacetamido)-3-(2-oxo-6-methylpyrimidin-4-ylthio)-methylceph-3-em4-carboxylic acid.   Novel cephalosporin compounds of the formula,

United States Patent [191 Sugimoto et al.

3,872,115 Mar. 18, 1975 CEPHALOSPORINS [75] Inventors: Keiichi Sugimoto,Kawanishi; Kunio Kobayashi; Kouji Nishijima, both of Osaka; ShiroMorimoto, Kobe, all of Japan [73] Assignee: Takeda Chemical Industries,Ltd.,

Osaka, Japan [22] Filed: May 31, 1972 [21] Appl. No.: 258,177

[30] Foreign Application Priority Data May 31. l97l Japan 46-38007 [52]US. Cl. 260/243 C, 424/246 [51] Int. Cl C07d 99/24 [58] Field of Search260/243 C [56] References Cited UNITED STATES PATENTS 3,663,540 5/1972Lemieux et a1. 260/243 C 3,673,l83 6/1972 Erickson 260/243 C PrimarrExaminer-Nicholas S. Rizzo Attorney, Agent, or Firm-Craig & Antonelli 57ABSTRACT Novel cephalosporin compounds of the formula.

wherein R is an acyl group, R and R represent hydrogen, a lower alkylgroup, carboxylic group, amino group, dimethylamino group orhydroxymethyl group, respectively, or R and R may be bonded to formNH-CH=N group. These cephalosporins have a broad antimicrobial spectrum.They are, in particular, effective against colitis germs (Escherichiacoli) at a lower concentration. Example thereof include 7-(2-thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid, 7-(phenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph- 3-em-4-carboxylic acid,7-(phenoxyacetamido)3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid and7-(2-thienyl-acetamido)-3-(2-oxo-6-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylic acid.

30 Claims, N0 Drawings CEPHALOSPORINS This invention relates to novelcephalosporin compounds and preparation thereof. More particularly, thisinvention relates to cephalosporin compounds of the formula:

wherein R is an acyl group, R and R represent hydrogen, a lower alkylgroup, carboxylic group, amino group, dimethylamino group, orhydroxymethyl group, respectively, or R and R may be bonded to form N-HCH=N group. The invention also relates to processes for producing thesame.

There have heretofore been known many cephalosporin C modified compoundsby converting the S-amino-S-carboxyvaleryl group at 7-p0sition ofcephalosporin C into various acyl groups and/or by converting theacetoxy group at 3-position into hydrogen, alkoxy group, substitutedthio group, quaternary ammonium group, etc. However, these well-knowncephalosporin compounds are not yet satisfactory in antimicrobialactivities against a wide variety of microorganisms. Hence, a compoundhas been sought after which has a broad antimicrobial spectrum and iseffective even at a lower concentration.

It has now been found that the novel cephalosporin compounds representedby the above formula (I) have broader antimicrobial spectra as comparedwith those of well-known cephalosporin derivatives. For example, theabove cephalosporin compounds (I) are quite effective against colitisgerms (E. 0011') at a remarkably low concentration, against whichcommercially available cephalosporins are not so effective. In addition,it is discovered that the cephalosporin compounds (I) of the presentinvention are also quite effective against various pathogenic bacteriaat a lower concentration as compared with well-known cephalosporins.

The acyl group represented by R in the cephalosporin compounds (I) ofthe present invention may be any one which is usable as the N-acyl groupof known cephalosporin or penicillin compounds. It may include aliphaticcarboxylic acid acyl groups such as hexanoyl, heptanoyl, octanoyl,cyclopentanoyl and the like, It further includes mono-substituted acetylgroups such as phenylacetyl, l-cyclohexenylacetyl, thienylacetyl,tetrazorylacetyl, cyanoacetyl, phenoxyacetyl, phenoxybutyloyl,nitrophenylacetyl, phenylpropionyl, butylthioacetyl, phenylthioacetyl,chlorophenylthioacetyl, benzylthioacetyl, phenetylthioacetyl,allylthioacetyl, pyridylthioacetyl, benzylthiopropionyl, etc.Alternatively, it may include disubstituted acetyl groups such asa-carboxyphenylacetyl, a-bromopropionyl, a-hydroxyphenylacetyl,a-sulfophenylacetyl, a-phenoxypropionyl, a-phenoxybutyloyl, etc.Furthermore, aromatic acyl groups such as benzoyl, 2,6-dimethoxybenzoyl, etc. or heterocyclic acyl groups such as-methyl-3-phenyl-4-isoxazolylcarbonyl, 3-0-chIorophenyl-S-methyl-4-isoxazolylcarbonyl, 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolylcarbonyl, etc.

may also be used. Further examples are amino groups containing acylgroups such as phenylglycyl, cyclohex- V enylglycyl, thienylglycyl,furylglycyl, cyclohexadienylglycyl, phenylmethylglycyl,carbamoylphenylacetyl, S-amino-5-carboxyvaleryl and so on. In addition,the acyl groups containing amino groups as set forth above may be thosewherein the amino groups are protected by carbobenzoxy, phthalyl,phenylthiocarbonyl, methylsulfonylethoxycarbonyl, isobornyloxycarbonyl,benzyloxycarbonyl, etc.

Among these acyl groups, the acyl group of the formula:

wherein R is phenyl, phenoxy, cyclohexenyl, thienyl,

phenylthio, or 3-amino-3-carboxypropyl, cyano, tetrazolyl, cyclohexylgroup; and R is hydrogen, or halogen atom, or amino, carboxyl, sulfo,carbamoyl, or hydroxy group, is most preferred.

In the above formula (I), R may be different from or the same as R,either of which may be selected from hydrogen atom, C to C lower alkylgroups such as methyl, ethyl, propyl and the like, carboxylic group,amino group, dimethylamino group, or hydroxymethyl group. Alternatively,R and R may be bonded to form NHCH=N group.

Such cephalosporin compounds (I) may be in the form of a salt with, forexample, sodium, potassium, magnesium, calcium, aluminum, triethylamineor the like.

The cephalosporin compounds (I) of the present invention can be producedby reacting a compound of the formula,

wherein R is as defined above, or a salt thereof with a compound of. theformula,

wherein R and R" are as defined above, or a salt thereof.

The compounds represented by the formulas (II) and (III) may be in theform of salts with metals such as sodium, potassium, calcium, aluminum,magnesium or the like. alternatively, they may be in the form of saltswith amines such as trimethylamine, triethylamine, tributylamine,triamylamine, pyridine or the like. Further, they may be in the form ofesters, particularly preferably easily hydrolyzable esters, such asmethyl, ethyl,

benzyl, methoxybenzyl, nitrobenzyl, phenyl, nitrophe- 3 nyl,methoxyphenyl, benzhydryl, trichloroethyl, trimethylsilyl,methylsulfonylethyl ester or the like.

The reaction between the compounds (II) and (III) is usually carried outin a suitable solvent. For example, alcohols such as methanol, ethanol,propanol and the like may be used. Alternatively, ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone and the like mayalso be used. Furthermore, dimethylformamide, dimethylsulfoxide,dioxane, chloroform, dichloromethane, dichloroethane or other organicsolvents in general which will not disturb the reaction may also beused. Among these, the solvents having strong polarity are particularlypreferred. Water alone or combined with the hydrophilic solvents amongthe organic solvents as mentioned above may also be used in the presentinvention. It is advantageous to maintain the pH value of the reactionsolution in the range from 2 to 10, more preferably, from 4 to 8. Forthat purpose, suitable buffer agents such as sodium acetate may be addedto the reaction solution to adjust the pH to a desired value. Thereaction temperature is not critical. Usually, however, the reaction iscarried out at an elevated temperature between and 70C. It is preferredto continue the reaction under such conditions from several hours to tenhours or more until the object 3- substituted cephem derivative (I) isobtained at a maximum yield.

The cephalosporin compounds (I) may alternatively be derived byacylating the compounds of the formula:

wherein R and R are as defined above. In these acylating reactions, thecarboxyl groups of the starting cephalosporin compounds (IV) may beprotected as in the form of an ester such as benzyl, phenylethyl,benzhydryl, trimethylsilyl ester or the like. The acylating reaction iseffected by reacting carboxylic acids to be incorporated includingcarboxylic acid residual groups or reactive derivatives thereof with7-amino-3substituted cephem derivatives (IV). The reactive derivativesof carboxylic acids to be incorporated may include acid halides such asacid chloride, acid bromide or the like. They further include acidanhydrides with alkyl carbonates, alkyl phosphates, other carboxylicacids or the like. They also include acid azides or active esters ofcarboxylic acids with pentachlorophenyl, p-nitrophenyl,N-hydroxysuccinic acid imide or the like. Alternatively, reactivederivatives formed between carboxylic acids and condensation agents suchas carbodiimide, N,N-carbonyl diimidazole, acetylene ether or the likemay also be used.

The acylation reaction may usually be conducted in a solvent. Suitablesolvents are organic solvents in general, including acetone, dioxane,chloroform, methylene chloride, tetrahydrofuran, ethers, ethyl acetateester or the like. Water or water-containing solvents may be also usabledepending on the kinds of the starting materials. The reactiontemperature is not critical, but the reaction may preferably beconducted under cooling or at room temperature. In case of the reaction,

B-methylsulwherein acids are byproduced, the reaction may preferably beconducted in the presence of bases such as alkali hydrogen carbonate,alkali carbonate, alkali hydroxide, or organic amines, e.g.triethylamine, pyridine, etc. If an ester of 7-amino-3-substitutedcephem derivative is used as the starting material, hydrolysis may beconducted after the reaction according to a method conventionallyapplied for hydrolysis of esters, e.g. treatment with acids or bases,etc. The reaction products can be separated according to conventionalmethods such as solvent extractions chromatography or the like. They mayfurther, if desired, be refined by way of recrystallization or the like.

In either method, the reaction solution obtained is concentrated underreduced pressure at a low temperature. Then, a portion of organicsolvents used in the reaction are removed by distillation. After theremaining liquid is adjusted to be acid, extraction is effected by theuse of organic solvents such as ethyl acetate, butanol, chloroform orthe like. The organic solvents are again distilled off by evaporationunder reduced pressure at a low temperature, until the crude powders ofthe object cephalosporin compounds are obtained.

The thus obtained crude products may be made into salts of sodium,potassium, organic amines or the like according to suitable methods.Such salts are watersoluble,-.so that they may highly be evaluated asantimicrobial agents in various fields.

The novel B-substituted cephem derivatives obtained according to theprocesses as described above are characteristic in that they possess asix mem bered heterocyclic group of the structure,

due to which they are found to have a stronger antimicrobial activityagainst both gram-positive and gramnegative bacteria of a wide range ascompared with cephalosporin compounds of the prior art.

The cephalosporin compounds (I) of the present invention are generallyadministered orally as well as in an injectable form, etc. in a similarmanner to the known cephalosporin preparations, but their dosage, dosageform, etc. vary with their substituent groups at 3-position and acylgroups at 7-pos'ition. For example, the effective dose of sodium7-(2-thienylacetamido)-3- (2-oxopyrymidin-4-ylthio)-methylceph3-em-4-carboxylate is about 0.25 g. to 1 g. per 4 to 6 hours for an adulthuman.

It is to be understood that the following examples are solely for thepurpose of illustration and not to be construed as limitations of thisinvention, and that many variations may be resorted to without departingfrom the spirit and scope of this invention. In this specificaon &Lg.,IYmg-1n urnlqvv umcgqvt L\m'p.Y7 and dc comp. are gram, milligram,milliliter, microgram, melting point" and decomposcd," respec tively.Temperatures are all uncorrected, and percentages are all on the weightbasis.

EXAMPLE 1 Sodium 7-(2-thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methyl-ceph-3-em-4-carboxylate a. 5 g. of sodium7-(2-thienylacetamido)- cephalosporanate and 1.6 g. of4-thiopyrimidin-2-one were dissolved in 100 ml. of dimethylsulfoxide.The solution was heated at 60C for 3 hours. The reaction solution wasadjusted to a pH between 1.0 and 2.0 by the addition of 1N hydrochloricacid and thereafter the reaction product was separated therefrom. Theproduct was suspended in a small amount of water, followed by adjustingthe pH of the suspension to 7.0 by sodium hydroxide and freeze-dried toobtain 35 g. of powders of sodium7-(2-thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methyl-ceph-3-em-4-carboxylate (yield 55%).

m.p.:180183C(decomp.) IR absorption spectrum (KBr disc):

1,760 cm (,B-lactam, 1,665 cm (CONH), 1,610 cm (COO) UV absorptionspectrum (pH 6.95 phosphate buffer solution): A 230 mu (6, 15,400); 275mu (e, 12,600); 297

mu (6, 13000) Elementary analysis:

Calculated for C,,,H, N S O Na.H O:

C, 42.86; H. 3.37; N, 11.11; S, 19.05 Found:

(142.95; H, 3.28; N, 10.58; S, 19.03

Antimicrobial spectra (mcg./ml.. agar dilution method) 1 Test Cepha-Cephab. 1.7 g. of 7-amino-3-(2-oxopyrimidin-4-ylthio)-methyl-ceph-3-em-4-carboxylic acid were dissolved in 5 ml. of 1N sodiumhydroxide under cooling on ice. Into this solution were added 1.68 g. ofsodium hydrogen carbonate and 10 ml. of ethyl ether. Then, 5 ml. ethylether solution containing 0.96 g. of Z-thienyl acetyl chloride wasfurther added dropwise for 10 minutes. The solution was stirred for 30minutes at the same temperature and further stirred for one hour at roomtemperature. The aqueous layer was separated from the reaction mixtureand 1N hydrochloric acid was added thereto to adjust it to a pH 1.0 to2.0 under cooling on ice. The precipitates were collected and subjectedto the same treatment as described in Example 1 (a). 2.3 g. of powdersof sodium 7-(2- thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylate were obtained (yield 91%).

c. After a similar manner to Example 1 (a), 3.2 g. ofB-methylsulfonyl-ethyl 7-(Z-thienylacetamido)-3-(2-oxopyrimidin4-ylthio)-methylceph-3-em-4- carboxylate was obtained from 5g. of ,B-methylsulfonylethyl 7-(2-thienylacetamido)cephalosporanate.This product was dissolved in 50 ml. of 50% aqueous tetrahydrofuransolution and 1N sodium hydroxide was gradually added thereto until pHbecame 8.0 The pH was then adjusted to 3.0 by 1N hydrochloric acid andtetrahydrofuran was removed by distillation under reduced pressure. Theprecipitated crystals were filtered and again 1N sodium hydroxide wasadded thereto. The aqueous solution, adjusted at pH 7.0, was freezedriedto obtain 2.4 g. of sodium 7-(2-thienylacetamido)-3-(2-oxopyrimldin-4-yltliio)-methylceph-3-em-4-carboxylate. The analytical values for this compoundwere identical with those for the compound obtained in Example 1 (a).

EXAMPLE 2 Disodium 7-(D-S-aminoadipoylamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate 2.27 g. of sodium3-acetoxymethyl-7-(D-5- aminoadipoylamido)cephalosporanate and 0.65 g.of 4-thiopyrimidin-2-one were dissolved in 30 ml. of dimethylsulfoxide.The solution was heated at 60C for 6 hours. The reaction liquid wasadjusted to pH 2.0 by the addition of0.5N hydrochloric acid. 2 Liters ofacetone were added to the reaction mixture. The precipitates weresuspended in a small amount of water, neutralized to pH 7.0 with sodiumhydroxide and freeze dried to obtain 2 g. of disodium 7-(D-5-aminoadipoylamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylate. m.p.: 230237C (decomp) IR absorptionspectrum (KBr):

1,760 cm (B-lactam), 1,665 cm (C()NH),

1,605 cm (COO Elementary analysis:

Calculated for C H N O S Na:

C, 40.98; H, 3.60; N, 13.28; S, 12.14

Found:

C, 39.11; H, 4.01; N, 13.13; S, 12.40

EXAMPLE 3 Disodium 7-(a-carboxyphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate:

1.43 g of sodium3-acetoxymethyl-7-(acarboxyphenylacetamido)cephalosporanate and 0.3 84

g. of 4-thiopyrimidin-2-one were dissolved in 10 ml. ofdimethylsulfoxide. This solution was heated at 50C for 8 hours. Thereaction liquid was then adjusted to pH 2.0 by addition of0.5Nhydrochloric acid. The precipitates were filtered and the powdersobtained were subjected to the same treatment as described in Example 2.0.4 g. ofdisodium 7-( a-carboxyphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-cm-4- carboxylate were obtainedin the form of powders.

m.p.: -l65C (decomp) IR absorption spectrum (KBr):

1,755 cm (B-lactam), 1,660 cm (CONH),

1,605 cm (COO') Elementary analysis:

Calculated for C H,,,N,,S O Na C, 46.14; H, 2.93; N, 10.15; S, 11.72Found:

C, 45.61; H, 3.78; N, 9.84; S, 11.05

Antimicrobial spectrum (meg/ml.)

Staphylococcus aureus BdC'lI/ILY snlmlzs H Proteus morgunu EXAMPLE 4Sodium 7-( phenylacetamido )-3-( 2-oxopyrimidin-4- ylthio)-methylceph-3-em-4-carboxylate:

a. 4.12 of sodium 3-acetoxymethyl7- (phenylacetamido)cephalosporanateand 1.28 g. of 4- thio-pyrimidin-Z-one were dissolved in 30 ml. ofdimethylsulfoxide. The solution was heated at 60C for 8 hours. Thereaction solution was similarly treated as described in Example 1 (a) toobtain 1.24 g. of powders of sodium7-(phenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em4-carboxylate.

m.p.: 205-210C (decomp.)

IR absorption spectrum (KBr):

1,760 cm (B-lactam), 1,660 cm (-CONH-'),

1,610 cm (COO) Elementary analysis:

Calculated for C ,H, N,S O Na:

C, 47.99; H, 3.57; N, 11.66; S, 13.35 Found:

C, 47.63; H, 3.98; N, 11.51; S, 12.66

b. 4.0 g. of sodium 7-(phenylacetamido)-3-bromomethylceph-3-em-4-carboxylate and 1.28 g. of 4-thiopyrimidin-2-onewere dissolved in 30 ml. of dimethylsulfoxide. The solution was heatedat 60C for 8 hours. The reaction solution was treated similarly as inExample 1 (a) to obtain 1.14 g. of powders of sodium7-(phenylacetamido)-3-(2-oxopyrimidin-4-ylthi0)-methylceph-3-em-4-carboxylate. The analytical values for this compoundwere identical with those for the compound obtained in Example 4 (a).

Antimicrobial spectrum (mcg./ml., agar dilution method) Test Cepha-Cepha- Organisms comloridine lothin pound Stuplx \'l0cocus aureus 209 P0.05 0.02 0.02

do. No.87 0.5 20 0.5 Bacillus sulllih's PC] 219 0.0l 0.05 0.02 Sart'inahm'a PC1 1001 0.1 0.05 0.1 Escherichia (O/i NIH] 5 10 PI'UIIUS rulgurin-Eb 51 5 5 2 Proteus mirubilis Eb 59 5 10 10 EXAMPLE 5 Antimicrobialspectrum (mcg./ml., agar dilution method) Test Cepha Y Cepha- Organismscomloridine lothin pound Slaplrvlucocrus aureus 209 P 0.01 0.02 0.02

do. No. 87 0.05 20 0.5 Bacillus sub/His PCl 219 0.()1 0.05 0.02 Sarcinaluleu PC1 1001 0.02 0.05 0.1 Escherichia vuh' NlHJ 1 10 20 Klelzriellupneunmniae Kb! 2 10 2 d. Sodium 7-( l-tetrazolylacetamido )-3-(2-0xopyrimidin-4-ylthio)-methylceph-3(-em-4- carboxylate m.p.: -157C(decomp.) IR absorption spectrum (KBr):

1,770 cm (B-1actam), 1,655 cm (CONH-),

1,610 cm (-COO) Elementary analysis:

Calculated for C H N S O Naz C, 38.13; H, 2.75; N, 29.66; S, 13.55Found:

C, 35.48; H, 3.75; N, 28.63; S, 13.01 e. Sodium7-(cyclohexylacetamido)-3-(2- oxopyrimidin-4-ylthio)-methylcepth-3-em-4-carboxylate:

m.p.: 194196C (decomp.) IR absorption spectrum (KBr):

1,760 cm (B-lactam), 1,660 cm (CONH),

1,610 cm (COO) Elementary analysis:

calculated for C20H23N4S205Nfl C, 49.37; H, 4.76; N, 11.52; S, 13.18Found:

C, 48.96; H, 4.24; N, 10.92; S, 12.71 f. Sodium7-(a-bromopropionylamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate m.p.: 162C(decomp.) IR absorption spectrum (KBr):

1,765 cm (B-lactam). 1,660 cm (CONH- 1,610 cm (-COO) Elementaryanalysis:

Calculated for C,,-,H,.,N.,S O BrNa:

C, 36.22; H, 2.82; N, 11.27; 5, 12.88 Found:

C, 35.11; H, 3.56; N, 11.12; S, 13.23

g. Sodium 7-[cyclohexenyl-(1,2-acetamido1-3-[2-oxopyrimidin-4-ylthio]-methylcepth-3-em-4- carboxylate m.p.: 155-l60C(decomp.) IR absorption spectrum (KBr):

1,765 cm (B-lactam), 1,665 cm (-CONH),

1,605 cm (COO) Elementary analysis:

Calculated for C20H21N4S205Na:

C, 49.48; H, 4.32; N, 11.54; S, 13.19

Found:

C, 48.92; H, 5.00; N, 11.13; S, 12.62

EXAMPLE 6 Sodium 7-(a-aminophenylacetamido)-3-(2- Found:

C, 46.80; H, 3.95; N, 13.68; S, 12.89

EXAMPLE 7 Sodium 7-(a-hydroxyphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate 4.05 g. of sodium3-acetoxymethyl-7-(a-hydroxyphenylacetamido)cephalosporanate and 1.28 g.of 4- thiopyrimidin-2-one were dissolved in 60 ml. of 50% aqueousdimethylsulfoxide. The solution was heated at 60C for 8 hours. Thereaction solution was treated similarly as described in Example 3 toobtain 3.0 g. of sodium 7-(a-hydroxyphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate.

m.p.: 2l0218C (decomp.) IR absorption spectrum (KBr):

1,755 cm (B-lactam), 1,660 cm" (-CONH),

1,610 cm (COO Elementary analysis:

Calculated for C H, N,S O Na:

C, 48.48; H, 3.66; N, 10.93; S, 12.94

Found:

C, 46.82; H, 3.76; N, 10.91; S, 12.47

EXAMPLE 8 Disodium 7-(a-sulfophenylacetamido)-3-(2-oxopyrimidin-4-y1thio)-methylceph-3-em-4- carboxylate 1.6 g. of disodium3-acetoxymethyl-7-(asulfonylphenylacetamido)cephalosporanate weredissolved in 50% aqueous dimethylsulfoxide. The solution was adjusted topH 6.5 by Dowex-50 (H )(trade name of Dow Chemical Co.) resin. Afterremoval of said resin, 0.4 g. of 4-thiopyrimidin-2-one were added to thesolution, which was then heated at 60C for 6 hours. The reactionsolution was poured into 200 ml. of tetrahydrofuran for precipitation.The precipitated honeylike substance was separated therefrom and, afterfurther addition of acetone thereto, 1.5 g. of disodium 7-(rx-sulfophenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylate were obtained.

m.p.: 2052l2C (decomp.) IR absorption spectrum (KBr):

1,755 cm" (B-lactam), 1,660 cm (CONH),

1,605 cm" (COO') Elementary analysis:

Calculated for C H -N S O Na C, 41.24; H, 2.77; N, 9.62; S, 16.51

Found:

C, 39.22; H, 3.62; N, 9.41; S, 15.90

EXAMPLE 9 Sodium 7-(2-thienylacetamido)-3-(2-oxor6-aminopyrimidin-4-ylthio)-methylceph-3 em-4- carboxylate 0.5 g. of sodium3-acetoxymethy1-7-(2 Antimicrobial spectrum Bacillus subtilis 0.5

EXAMPLE 10 Sodium 7-(2-thienylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate 0.5 g. ofsodium 34-acetoxymethyl-7-(2- thienylacetamido)cephalosporanate and 0.17g. of 4- thio-5-methylpyrimidin-2-one were dissolved in 5 ml. of aqueousdimethylsulfoxide. The solution was heated at 60C for 5 hours. Thereaction solution was treated similarly as described in Example 1 (a) toobtain 0.42 g. of powders of sodium 7-(2-thienylacetamido)-3-(2-oxymethylpyrimidin-4-ylthio)- methylceph-3-em-4-carboxylate. m.p.:2062l5C (decomp.) IR absorption spectrum (KBr):

1,760 cm (B-lactam), 1,655 cm (-CONH),

1,610 cm (COO) Elementary analysis:

Calculated for C H N S O Na:

C, 45.59: H, 3.42; N, 11.19; S, 19.22

Found C, 44.26; H, 4.16; N, 10.54; S, 18.79

EXAMPLE 11 Sodium 7-(2-thienylacetamido)-3-(2-oxopurin-6-ylthio)-methylceph-3-em-4-carboxylate 0.5 g. of sodium3-acetoxymethyl-7-(2- thienylacetamido)cephalosporante and 0.2 g. ofammonium 6-thiopurin-2-one were dissolved in ml. of dimethylsulfoxide.The solution was heated to 60C for 5 hours. The reaction solution wastreated similarly as described in Example 1 (a) to obtain powders ofsodium 7-(2-thienylacetamido)-3-(2-oxopurin-6-ylthio)-methylceph-3-em-4-carboxylate. m.p.: 225-227C (decomp.) IR absorptionspectrum (KBr):

1,755 cm (B-lactam), 1,680 cm (CONH)),

1,610 cm COO) Elementary analysis:

Calculated for C H, N S O Na:

C, 43.34; H, 2.87; N, 15.96; S, 18.27 Found:

C, 41.42: H, 3.63; N, 15.72; S, 17.94 According to a similar procedureas described above, the following compounds were synthesized. a. Sodium7-(2-thienylacetamido)-3-(2-oxo-6-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate m.p.: l96-205C(decomp.) IR absorption spectrum (KBr):

1,765 cm (B-lactam), 1,660 cm (COHN),

1,605 cm"(COO Elementary analysis:

Calculated for C ,,H N S O Na:

C, 45.59; H, 3.42; N, 11.19; S, 19.22 Found:

C. 45.26; H, 4.56;N, 10.92; S, 18.98

Antimicrobial spectrum (mcg./m1., agar dilution method) Test compoundCephloridine Cepha- Organisms lothin 209 P 0.05 No. 87 0.]

Staphylococcus aureus d o. Bacillus sublilis PCl 219 Sarcl'na Iulea PC11001 Escherichia coli NlHJ Klebsie/Ia pneumoniue Kbl Proteus vulgaris Eb51 Proleus mirabilis Eb 59 1 Proteus murganii Eb 54 l IR absorptionspectrum (KBr):

1,765 cm (,B-lactam), 1,665 cm (-COHN-),

1,610 cm* (COO) Elementary analysis:

Calculated for C19H 4N4S3O7Na2:

C, 41.30; H, 2.55; N, 10.14; S, 1741 Found:

C, 39.65; H, 3.84; N, 9.46; S, 16.72 (1. Sodium7-(2-thienylacetamido)-3-(2-oxo-5,6-dihydropyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate:

m.p.: 211218C (decomp.) IR absorption spectrum (KBr):

1,760 cm" (B-lactam), 1,665 cm (COHN),

1,610 cm (-COO') Elementary analysis:

Calculated for C H N S O Na:

C, 44,26; H, 3, 48, N, 11, 48, S, 19,67 Found:

C, 39.78; H, 4.12; N, 10.11; S, 17.92 e. Sodium7-(2-thienylacetamido)-3-(2-oxo-5-hydroxymethylpyrimidin-4-ylthio)-methyl-ceph-3-em- 4-carboxylate m.p.:186-l92C (decomp.) IR absorption spectrum (KBr):

1,765 cm (B-lactam), 1,660 cm (COHN),

1,605 cm (COO) Elementary analysis:

Calculated for C H, N S O Na:

C, 44.18, H, 3.32; N, 10.85; S, 18.62

Found:

C, 43.57; H, 4.28; N, 9.64; 5, 18.34

EXAMPLE 12 Sodium 7-(a-carbamoylphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylcepth-3-em-4- carboxylate a. 3 g. of sodium3-acetoxymethyl-7-(acarbamoylphenylacetamido)cephalosporanate and 850mg. of 4-thiopyrimidin-2-one were dissolved in 30 ml. ofdimethylsulfoxide. The solution was adjusted to pH 7.0 by 1N aqueousammonia and heated at 60C for 3 hours. The reaction product was treatedsimilarly as described in Example 1 (a) to obtain powders of sodium7(a-carbamoylphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylate.

m.p.: 190l95C (decomp.)

IR absorption spectrum (KBr):

1,750 cm (,B-lactam), 1,680 cm (COHN- 1,610 cm" (COO) Elementaryanalysis:

Calculated for C21H1gN5S20 Na:

C, 48.18; H, 3.47; N, 13.38: S, 12.25

Found:

C, 47.62; H, 3.96; N, 13.12; S, 11.86

Antimicrobial spectrum Bacillus subtilis 0.05

b. 1.7 g. of 7-amino-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid was suspended in 20 ml. ofdichloromethane. While this suspension was cooled on ice, 1.25 g. oftriethylamine were added and dissolved therein. To this solution wasfurther added 15 g. of paranitrophenyl ester of a-carbamoylphenyl aceticacid. The solution was stirred under ice-cooling for 30 minutes andfurther stirred at room temperature for one hour. 20 ml. of water wereadded to the reaction solution under cooling on ice and pH thereof wasadjusted to 1.0 to 2.0 The precipitated crystals were collected byfiltration and subjected to the same treatment as described in Example 1(a) to ,obtain powders of sodium 7-(a-carbamoylphenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylcepth-3-em-4- carboxylate.

EXAMPLE 13 Sodium 7-(2-thienylacetamido)-3-[ 2-oxo-( l-B-D-ribofuranosyl)pyrimidin-4-ylthio]-methy1ceph-3-em-4- carboxylate g. ofsodium 7-(2-thienylacetamido)cephalosporonate and 3.3 g. of 4-thio-(l-,8-D-riboturanosyl)- pyrimidin-2-one were dissolved in 50 ml. ofwater. The solution was heated at 60C for 3 hours. The reaction solutionwas adjusted to pH 2.0 by addition of 0.5N hydrochloric acid. Theprecipitated crystals were separated therefrom and neutralized to pH 6.5by 0.5N sodium hydroxide. They were then freeze-dried to obtain 4.5 g ofwhite powders.

m.p.: l55160C (decomp.) IR absorption spectrum (KBr):

1770 cm (B-lactam), 1670 cm (-COHN-),

1620 cm' (-COO) UV absorption spectrum (pH 6.95, phosphate buf fer):Amax 230 my. (6, 17300), 277 my. (6, 13300),

302.5 m,u. (6, 15200) Elementary analysis:

Calculated for C H N S O Na3H O: C, 41.06; H, 4.16; N, 8.23; S, 14.28

Found:

C, 41.11; H, 3.75; N, 7.88, S, 14.68

EXAMPLE 14 Sodium 7-(2-thienylacetamido)-3-(2-oxo-5-dimethylaminopyrimidin-4-ylthio)-methylceph-3-em- 4-carboxylate 5 g. ofsodium 7-(2-thieny1acetamido)cephalosporanate and 2.2 g. of4thio-5-dimethylaminopyrimidin- 2-one were dissolved in 50 ml. 50%aqueous dimethylformamide. The solution was heated at 60C for 8 hours.The powders obtained by drying the reaction solution under reducedpressure were suspended in 100 m1. of water and neutralized to pH 6.5with sodium hydrogen carbonate. After removal of insoluble substances byfiltration, the filtrate was freeze-dried to obtain 1.7 g. of lightyellow powders.

m.p.: l65170C (decomp.) 1R absorption spectrum (KBr):

1,700 cm (B-lactam), 1,675 cm (CONH) 1,615 cm (COO) Elementary analysis:

Calculated for C H N S O Na:

C, 45.02; H, 3.75; N, 13.13; S, 18.01

aminopyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate 5 g. of sodium7-(2-thienylacetamido)cephalosporanate and 2.5 g. of4-thio-5-aminopyrimidin-2-one were dissolved in 50 ml. of 50% aqueousdimethylform- 6 amide. The solution was heated at 60C for 8 hours. Thepowders obtained by drying the reaction solution under reduced pressurewere suspended in 100 m1. of water and neutralized to pH 6.5 by sodiumhydrogen carbonate. After removal of insolublesubstances by filtration,the filtrate was freeze-dried to obtain 1.8 g. of light yellow powders.

m.p.: 140-l50C (decomp.) IR absorption spectrum (KBr):

1,760 cm (B-lactam), 1,660 cm (CONH),

1,605 cm (COO) Elementary analysis:

Calculated for C H N S O Na:

C, 43.11; H, 3.22; N, 13.96; S, 19.77 Found:

C, 42.86; H, 3.96; N, 13.71; S, 19.54

EXAMPLE 16 Sodium 7-(a-carbamoylphenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate 5 g. of sodium7-(a-carbamoylphenylacetamido)- cephalosporanate were dissolved in 50ml. of water. After further addition of 3 g. methylpyrimidin-Z-one andml. of dimethylsulfoxide, the solution was heated at 60C for 8 hours.The reaction solution was concentrated to dryness under reducedpressure. The residue was shaken with a mixture of 50 m1. of water and50 ml. of ethyl acetate. The aqueous layer was washed with 50 ml.portion each of ethyl acetate for three times. The aqueous layer wasthen freeze-dried to obtain light yellow powders, which were thereaftersubjected to chromatography by passing column-wise over Amberlite XAD-Z(trade name of ROhm and Haas Co.) to obtain 1.7 g. of white powders.

m.p.: 169-175C (decomp.) IR absorption spectrum (KBr):

1.770 cm (B-lactam), 1,610 to (COHN-, -COO Elementary analysis:

Calculated for C H N S O Na:

C, 49.16; H, 3.72; N, 13.03; S, 11.91 Found:

C, 48.51; H, 4.45; N, 12.76; S, 11.39

EXAMPLE 17 Disodium 7-(a-carboxylphenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3 em-4- carboxylate 5 g. of sodium7-(a-carboxyphenylacetamido)- cephalosporanate and 1.5 g. of 4-thio-5-methylpyrimidin-2-one were dissolved in 75 ml. of 70% aqueousdimethylformamide. The solution was heated at 60C for 8 hours. Thereaction solution was dried under reduced pressure. The residues wereadded with 50 ml. of water and neutralized to pH 6.5 by sodium hydrogencarbonate. After removal of insoluble substances by filtration, thefiltrate was adjusted to pH 2.0 by addition of 0.5N hydrochloric acid.The precipitated crystals were separated therefrom and adjusted to pH6.5 by 0.5N sodium hydroxide. After freeze-drying 1.8 g. of light yellowpowders were obtained.

m.p.: -100C (decomp.)

IR absorption spectrum (KBr):

1,750 cm (B-lactam), 1,675 cm (CONH),

1,620 cm (COO) Elementary analysis:

Calculated for C H, N,S O Na C, 47.14; H, 3.21; N, 9.99; S, 11.43

Found:

C, 46.39; H, 3.99; N, 9.54; S, 1087 Antimicrobial spectrum (mcg./ml.,agar dilution pneunmniae Kbl EXAMPLE 18 Disodium7-(a-sulfophenylacetamido)-3-(2-oxo-5methylpyrimidin-4-ylthio)-methylceph-3-em4- carboxylate 3.3 g. of sodium7-(a-sulfophenylacetamido)- cephalosporanate and 0.53 g. of 4-thio-5-methylpyrimidin-Z-one were dissolved in 40 ml. of 70% aqueousdimethylformamide. The solution was heated at 60C for 8 hours. Thereaction solution was poured into 400 ml. of tetrahydrofuran. Theprecipitated honey-like substance was separated therefrom. It wasfurther washed with 100 ml. of tetrahydrofuran and 100 ml. of acetone.1.4 g. of light yellow powders were obtained.

m.p.: 115120C (decomp.)

IR absorption spectrum (KBr):

1,760 cm (,B-lactam), 1,670 cm (CONH),

1,610 cm (-COO'), 1,040 cm (SO Elementary analysis:

Calculated for C H,,,N,S O,,Na

C, 42.21; H, 3.01; N, 9.38; S, 16.08 Found:

C, 41.72; H, 3.95; N, 8.79; S, 15.67

EXAMPLE l9 Trifluoroacetate of 7-(a-aminophenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylic acid 5 g.of sodium 7-[a-(isobornyloxycarbonyl)aminophenylacetamido]cephalosporanate and 3.5 g.of 4-thio-5-methylpyrimidin- 2-one were dissolved in 200 ml. of 70%aqueous dimethylsulfoxide. The solution was heated at 60C for 5 hours.The reaction solution was dried under reduced pressure. 50 ml. of waterand 50 ml. of ethyl acetate were added to the dried residue. Aftershaking the mixture, the aqueous layer was washed three times with 50ml. each portion of ethyl acetate. The aqueous layer was adjusted to pH2.0 by addition of 0.5N hydrochloric acid. 50 ml. of ethyl acetate wasfurther added thereto and the mixture was shaken. The ethyl acetatelayer was, after washing with water, neutralized to pH 6.5 by 0.5Nsodium hydrogen carbonate, while the aqueous layer was freezedried toobtain 2 g. of light yellow powders.

0.5 g. of the thus obtained sodium 7-[a-(isobornyloxycarbonyl)aminophenylacetamido]-3-(2- 16oxo-S-methylpyrimidin-4-ylthio)methylceph-3-em-4- carboxylate wasdissolved in 10 ml. of trifluoroacetic acid. The solution was furtheradded with 0.5 m1. of anisole and stirred at room temperature for onehour. The reaction solution was poured into 50 ml. of ethyl ether. Theprecipitates were collected by filtration and washed with 50 ml. ofethyl ether to obtain 0.4 g. of white powders.

m.p.: 110115C (decomp.) IR absorption spectrum (KBr):

1,770 cm (,8-lactam),' 1,675 cm (COOH).

1,695 cm (CONH) Elementary analysis:

Calculated for C ,H ,N =,S O .CF CO. .H:

C, 45.92; H, 3.66; N, 11.64; S 10.64

Found:

C, 45.39; H, 3.98; N, 11.02; S, 10.18

EXAMPLE 20 Trifluroacetate of 7-amino-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylic acid 5 g. ofsodium 7-(isobornyloxycarbonyl)aminocephalosphoranate and 2 g. of4-thio-5-methylpyrimidin- 2-one were dissolved in 50 ml. of aqueousdimethylsulfoxide. The solution was heated at- 60C'for 10 hours. Thereaction solution was dried under reduced pressure. 50 ml. of water and50 ml. of ethyl acetate were added to the dried residue and the mixturewas agitated. The aqueous layer was further washed with 50 ml. eachportion of ethyl acetate for three times. The aqueous layer was adjustedto pH 2.0 by addition of 0.5N hydrochloric acid. 50 ml. of ethyl acetatewas further added to the aqueous layer and the mixture was shaken. Theethyl acetate layer was, after washing with water, neutralized to pH 6.5by addition of 0.5N sodium hydrogen carbonate, while the aqueous layerwas freeze-dried to obtain 3.5 g. of light yellow powders.

1 g. of the thus obtained sodium 7-[(isobornyloxycarbonyl)amino]-3-(2-oxo-5-methylpyrimidin-4-ylthio)methylceph-3-em-4- carboxylate was dissolved in20 m1. of water. The solution was adjusted to pH 2.0 by addition of 0.1Nhydrochloric acid under cooling on ice. The mixture was shaken with 30ml. of ethyl acetate for three times. The ethyl acetate layer were,after washing with water, dried under reduced pressure. The residue wasdissolved in 10 ml. of trifluoroacetic acid. The solution, afteraddition of 0.5 ml. of anisole, was stirred at room temperature for onehour. The reaction solution was dried under reduced pressure. 50 ml. ofethyl ether was added to the residue and the mixture was stirredthoroughly. 0.73 g. of white powders were obtained.

m.p.: -110C (decomp.)

IR absorption spectrum (KBr) 1,780 cm (B-lactam), 1,730 cm (CONH,--COOH), 1.610 cm, 1,670 cm- (CONH) Elementary analysis:

Calculated for C,;,H N S O,.CF COOH:

C, 39.65; H, 3.52; N, 12.33, S, 14.10 Found:

C,40.84; H, 3.93; N, 12.14; S, 14.12 What we claim is: l. A compound ofthe formula wherein R is phenyl, phenoxy, cyclohexenyl, thienyl.phenylthio, 3-amino-3-carboxypropyl, cyano, tetrazo lyl, or cyclohexylgroup; and R is hydrogen, amino, carboxyl, sulfo, carbamoyl, halogen orhydroxy group, R and R represent hydrogen, a alkyl group having one tofour carbon atoms, carboxylic group, amino group, dimethylamino group,or hydroxymethyl group, respectively, or R and R may be bonded to form-N- HCH=N group or a salt thereof.

2. A compound according to claim 1, wherein R is Z-thienylacetyl group.

3. A compound according to claim 1, wherein R is phe'nylacetyl group.

4. A compound according to claim 1, wherein R is phenylthioacetyl group.

5. A compound according to claim 1, wherein both R and R are hydrogenatoms.

6. A compound according to claim 1, wherein one of R and R is methylgroup and the other is hydrogen atom.

7. A compound claimed in claim 1, namely 7-(2-thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.

8. A compound claimed in claim 1, namely 7-(phenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.

9. A compound claimed in claim 1, namely 7-(phenoxyacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.

10. A compound claimed in claim 1, namely 7-(2-thienylacetamido)-3-(2-oxo-6-methylpyrimidin-4-ylthio)-methylceph3-em-4-carboxylic acid.

11. A compound according to claim 1, namely 7-(acarboxyphenylacetamido)-3-(2-oxo5-methylpyrimidin-4-ylthio-methylceph-3-em-4- carboxylic acid.

12. A compound according to claim 1, wherein R is phenyl or thienyl.

13. A compound according to claim 12, wherein R is phenyl.

14. A compound according to claim 1, wherein R is amino, carboxyl orsulfo.

15. A compound according to claim 14, wherein R is carboxyl.

16. A compound according to claim 1, wherein R is methyl.

17. A compound according to claim 1, wherein R is hydrogen.

18. A compound according to claim 1, wherein said compound is an acid ora salt of sodium, potassium, magnesium, calcium, aluminum ortriethylamine.

19. A compound according to claim 1, wherein R is selected from thegroup consisting of phenyl, phenoxy, thienyl and phenylthio and furtherwherein R is hydrogen.

20. A compound according to claim 19, wherein R is phenyl.

21. A compound according to claim 19, wherein R" is phenoxy.

22. A compound according to claim 19, wherein R is thienyl.

23. A compound according to claim 19, wherein R is phenylthio.

24. A compound according to claim 19, wherein both R and R" are hydrogenatoms.

25. A compound according to claim 19, wherein one of R and R is a methylgroup and the other is a hydrogen atom.

26. A compound according to claim 19, wherein R is methyl.

27. A compound according to.claim 19, wherein R is hydrogen.

28. A compound according to claim 19, wherein said compound is an acidor a salt of sodium, potassium, magnesium, calcium, aluminum or triethylamine.

29. A compound according to claim 19, namely disodium7-(a-carboxyphenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4- carboxylate.

30. A compound according to claim 19, namely 7-(2-thienylacetamido)-3-(2-oxo-5-methyl-pyrimidin-4-

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1, whereinR1 is 2-thienylacetyl group.
 3. A compound according to claim 1, whereinR1 is phenylacetyl group.
 4. A compound according to claim 1, wherein R1is phenylthioacetyl group.
 5. A compound according to claim 1, whereinboth R2 and R3 are hydrogen atoms.
 6. A compound according to claim 1,wherein one of R2 and R3 is methyl group and the other is hydrogen atom.7. A compound claimed in claim 1, namely7-(2-thienylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.
 8. A compound claimed in claim 1, namely7-(phenylacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylicacid.
 9. A compound claimed in claim 1, namely7-(phenoxyacetamido)-3-(2-oxopyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.
 10. A cOmpound claimed in claim 1, namely7-(2-thienylacetamido)-3-(2-oxo-6-methylpyrimidin-4-ylthio)-methylceph-3-em-4-carboxylic acid.
 11. A compound according to claim 1, namely 7-(Alpha-carboxyphenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio-methylceph-3-em-4-carboxylicacid.
 12. A compound according to claim 1, wherein R4 is phenyl orthienyl.
 13. A compound according to claim 12, wherein R4 is phenyl. 14.A compound according to claim 1, wherein R5 is amino, carboxyl or sulfo.15. A compound according to claim 14, wherein R5 is carboxyl.
 16. Acompound according to claim 1, wherein R2 is methyl.
 17. A compoundaccording to claim 1, wherein R3 is hydrogen.
 18. A compound accordingto claim 1, wherein said compound is an acid or a salt of sodium,potassium, magnesium, calcium, aluminum or triethylamine.
 19. A compoundaccording to claim 1, wherein R4 is selected from the group consistingof phenyl, phenoxy, thienyl and phenylthio and further wherein R5 ishydrogen.
 20. A compound according to claim 19, wherein R4 is phenyl.21. A compound according to claim 19, wherein R4 is phenoxy.
 22. Acompound according to claim 19, wherein R4 is thienyl.
 23. A compoundaccording to claim 19, wherein R4 is phenylthio.
 24. A compoundaccording to claim 19, wherein both R2 and R3 are hydrogen atoms.
 25. Acompound according to claim 19, wherein one of R2 and R3 is a methylgroup and the other is a hydrogen atom.
 26. A compound according toclaim 19, wherein R2 is methyl.
 27. A compound according to claim 19,wherein R3 is hydrogen.
 28. A compound according to claim 19, whereinsaid compound is an acid or a salt of sodium, potassium, magnesium,calcium, aluminum or triethyl amine.
 29. A compound according to claim19, namely disodium 7-( Alpha-carboxyphenylacetamido)-3-(2-oxo-5-methylpyrimidin-4-ylthio)-methylceph-3-em-4-carboxylate.
 30. A compound according to claim 19, namely7-(2-thienylacetamido)-3-(2-oxo-5-methyl-pyrimidin-4-ylthio)-methylceph-3-em-4-carboxylicacid.